This invention relates to a pharmaceutical delivery system for obtaining a controlled ratio of antioxidants. It further relates to a principle of antioxidant levels in blood plasma.
The present invention proposes a pharmaceutical delivery system for oral delivery of the antioxidants vitamin C and vitamin E to obtain high concentrations thereof and a controlled ratio between the vitamins in blood plasma in humans and animals.
It is an object of the present invention to provide a method for the prevention or treatment of arteriosclerosis or other diseases or conditions where reactive oxygen species are involved using a delivery system for obtaining a controlled ratio of antioxidants in blood plasma.
Free radical reactions appear in the cells of all mammalian bodies. Free radical derivatives of oxygen are of particular importance because of the use of oxygen to generate energy in the body. In the cellular processes, oxygen is reduced to water through the addition of 4 electrons, a process that is tightly controlled (1). Reactive oxygen species (ROS) are intermediary products produced during this process. These include superoxide anions, hydrogen peroxide, and hydroxyl radicals. The ROS are highly reactive and modify important cellular macromolecules (2). ROS initiate or accelerate disease processes.
The formation of ROS can occur as part of many cellular processes including mitochondrial respiration, immune cell responses, cell injury, heat, radiation of many origins, from metabolism of drugs and other chemicals. ROS are thought to be involved in almost all disease processes and the ageing process. For example, modification can occur to lipids in the LDL (light density lipoprotein) particle in the blood (3). This modification leads to increased formation of fatty streaks in the arterial wall and subsequent formation of arterisclerotic plaques (3b, 4) which can compromise blood supply to organs, causing manifest disease, e.g. coronary heart attack.
The body and its cells have several mechanisms to control the effects of ROS. The general term of such mechanisms is antioxidants. Antioxidants include enzymes, substances produced in the body and substances that are only found in food. Examples of the latter are antioxidant vitamins (E, C, A) and similar substances (flavonoids, lycopene, beta-carotene). The substances have different properties, some being water-soluble others being fat-soluble (2).
During the last decades, evidence has gathered linking both high intake of food rich in antioxidants, and intake of supplements containing antioxidant vitamins to reduce incidence of cancer and arteriosclerosis (5).
A particularly important part of the lipid phase is the LDL particle (low density lipoproteins). These particles are produced in the liver and are responsible for transport of lipids, particularly cholesterol. These particles are taken up by cells by a protein moiety APO-B100, an uptake which is feed-back inhibited. If LDL is oxidised, it cannot be taken up, but is then devoured by monocyte derived macrophages with no feed-back inhibition. Macrophages can transform into foam cells when large amounts of LDL are taken up. The foam cells deposit in the arterial wall and contribute to the development of arteriosclerotic plaques (4).
Water-soluble antioxidants are taken up quickly, but are also eliminated quickly from the body by urinary excretion (6). Fat-soluble antioxidants are taken up more slowly and eliminated slowly from the body (7). This means that the concentration ratio of e.g. a water-soluble and a fat-soluble antioxidant vitamin will vary after intake.
Water-soluble and fat-soluble antioxidants are found, respectively, in the water phase and in the lipid phase of the body. In the transition phase between the lipid and water phases there is co-operation between the water and the fat-soluble antioxidants. An example of this is the interaction between vitamin C and vitamin E in the transition between the LDL particle and the water phase of the blood (8, 9). Vitamin E is the most important antioxidant in the LDL particle.
When vitamin E is oxidized in the LDL particle, a tocopheryl radical is generated. This radical can elicit lipid peroxidation or protein oxidation and can thus result in the oxidation of the LDL particle with the consequences described above (8). Vitamin C, ascorbic acid (AA), can prevent this process by interacting with the tocopheryl radical. This results in reduction of the tocopheryl radical to tocopherol and the formation of oxidised vitamin C, dehydro-ascorbic acid, DHAA (10). DHAA is taken up by the liver and reduced to vitamin C (11).
U.S. Pat. No. 5,897,879 discloses a sustained-release pharmaceutical delivery system for the administration of an antioxidant drug to a patient in need of such drug, wherein the said delivery system comprises the said drug in combination with a matrix, the said matrix comprising a polymer selected from the group consisting of a polymer which does not interact with the said drug and a mixture of such polymers, and the said polymeric matrix is present in amounts from about 20% (w/w) to about 80% (w/w). The drug can inter alia be vitamin E, vitamin C or a combination thereof. In the case of combination both drug components have a sustained-release form, and they are released together. This known system does not give effective high, constant concentrations of vitamin C and E.
WO 97/00672 discloses an effervescent composition comprising at least one active ingredient selected from the group consisting of a nutritional supplement, a dietary supplement and combinations thereof in amounts sufficient to provide a dosage form of the said active ingredient as few as once in a 24hour period, the said active ingredients being both a free form component and a microencapsulated component which has sustained-release properties, and an effective amount of an effervescent agent. The active agent is selected from the group consisting of camitine, calcium, magnesium, ascorbic acid, vitamin E and combinations thereof. The active agents are micro-encapsulated together. This known composition provides immediate and sustained release of both vitamin C and vitamin E. The vitamins are released together from the same delivery principle(s), and they do not provide a high, constant vitamin concentration, in the preferred ratio in the blood plasma.
EP 176772 discloses a process for increasing the delayed-release activity of vitamin C and vitamin E by incorporating both vitamins in a neutral oil and encapsulating the oil. Both vitamins are present in the same delivery principal.
EP 0820703 discloses compositions for nutritional integration comprising hydrosoluble vitamins and liposoluble vitamins, characterised in that the hydrosoluble vitamins have a prolonged-release formulation and the liposoluble vitamins have a rapid-release formulation.
A large controlled trial over more than 5 years showed no effect of a 50-mg tocopherol dose (12).
A controlled release formulation of vitamin C and E failed to give the expected increase in vitamin E plasma concentrations whereas it produced a more constant and thus favourable vitamin C concentration (13).
A study designed to test the effect of ascorbic acid, selenium, xcex1-tocopherol and xcex2-carotene on the oxidation resistance of VLDL and LDL (14) demonstrated that the oxidation resistance of atherogenic lipoproteins in human plasma required the combined elevated levels of selenium and antioxidative vitamins or elevated doses of xcex2-carotene and xcex1-tocopherol.
The present invention solves the problem of providing high concentrations of vitamin C and E in the preferred ratio by using a pharmaceutical delivery system for oral delivery of vitamin C and vitamin E to obtain high concentrations thereof in a controlled ratio in blood plasma in humans or animals by a delivery system with slow release of vitamin C and plain release of vitamin E.
The present invention seeks to provide a method of providing oxidation resistance without the use of selenium or xcex2-carotene by providing high concentrations of vitamin C and E at a controlled ratio in blood plasma.
The present invention relates to a pharmaceutical delivery system for oral delivery of the antioxidants vitamin C and vitamin E to obtain high concentrations thereof and a controlled ratio between vitamin C and vitamin E in blood plasma in humans or animals, characterised in that it has a slow release formulation of vitamin C and a plain release formulation of vitamin E.
The invention relates to a method of treating or preventing oxidative stress disorders and associate diseases comprising the administration to an individual a combination of vitamin C and vitamin E in sufficient amounts so as to raise, within 8 weeks of the first administration, the concentration of said vitamins in blood plasma sufficiently and to a ratio of from 1:1 to 3:1, preferably 2.2:1.
The invention further relates to a method of treating or preventing oxidative stress disorders and associate diseases comprising the daily administration to an individual at least one dosage unit comprising a combination of vitamin C and vitamin E in sufficient amounts so as to raise the concentration of said vitamins in blood plasma sufficiently and to a controlled ratio wherein said vitamin C is formulated in a slow-release preparation and vitamin E is formulated in plain-release formulation.
Furthermore, the invention relates to the use of a combination of vitamin C. and vitamin E for the preparation of a drug or drug system for treating or preventing atherosclerosis or other diseases or conditions responsive to antioxidants, wherein said vitamins are incorporated in the patients blood plasma in high concentrations and in a controlled ratio characterised in that the drug or drug system has a slow release of vitamin C and a normal release of vitamin E.